Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations
Authors: Morgan N. Similuk, Jia Yan, Rajarshi Ghosh, Andrew J. Oler, Luis M. Franco, Michael R. Setzer, Michael Kamen, Colleen Jodarski, Thomas DiMaggio, Joie Davis, Rachel Gore, Leila Jamal, Adrienne Borges, Nicole Gentile, Julie Niemela, Chenery Lowe, Kathleen Jevtich, Yunting Yu, Haley Hullfish, Amy P. Hsu, Celine Hong, Patricia Littel, Bryce A. Seifert, Joshua Milner, Jennifer J. Johnston, Xi Cheng, Zhiwen Li, Daniel Veltri, Ke Huang, Krishnaveni Kaladi, Jason Barnett, Lingwen Zhang, Nikita Vlasenko, Yongjie Fan, Eric Karlins, Satishkumar Ranganathan Ganakammal, Robert Gilmore, Emily Tran, Alvin Yun, Joseph Mackey, Svetlana Yazhuk, Justin Lack, Vasudev Kuram, Wenjia Cao, Susan Huse, Karen Frank, Gary Fahle, Sergio Rosenzweig, Yan Su, SuJin Hwang, Weimin Bi, John Bennett, Ian A. Myles, Suk See De Ravin, Ivan Fuss, Warren Strober, Bibiana Bielekova, Adriana Almeida de Jesus, Raphaela Goldbach-Mansky, Peter Williamson, Kelly Kumar, Caeden Dempsy, Pamela Frischmeyer-Guerrerio, Robin Fisch, Hyejeong Bolan, Dean D. Metcalfe, Hirsh Komarow, Melody Carter, Kirk M. Druey, Irini Sereti, Lesia Dropulic, Amy D. Klion, Paneez Khoury, Elise M. O' Connell, Nicole C. Holland-Thomas, Thomas Brown, David H. McDermott, Philip M. Murphy, Vanessa Bundy, Michael D. Keller, Christine Peng, Helen Kim, Stephanie Norman, Ottavia M. Delmonte, Elizabeth Kang, Helen C. Su, Harry Malech, Alexandra Freeman, Christa Zerbe, Gulbu Uzel, Jenna R.E. Bergerson, V. Koneti Rao, Kenneth N. Olivier, Jonathan J. Lyons, Andrea Lisco, Jeffrey I. Cohen, Michail S. Lionakis, Leslie G. Biesecker, Sandhya Xirasagar, Luigi D. Notarangelo, Steven M. Holland, Magdalena A. Walkiewicz
Journal: Journal of Allergy and Clinical Immunology (2022)

BackgroundProspective genetic evaluation of patients at this referral research hospital presents clinical research challenges.ObjectivesThis study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health.MethodsThis study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity.ResultsProbands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option.ConclusionsThis program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale. Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.